Chapter 36

Inherited metabolic disorders

Definitions and management

Emergency regimens for IMD

Phenylketonuria

Refsum’s disease

Definitions and management

Definitions

Metabolism: cellular biochemical reactions that occur within the body. This involves the breakdown (catabolism) and formation (anabolism) of chemical compounds.

Metabolic pathways: sequence of chemical reactions of metabolism.

Enzymes: proteins that control the chemical reactions (or steps) in a metabolic pathway.

Cofactors: ‘helper molecules’ that assist the protein in the biochemical reaction. These are often vitamins.

Inherited metabolic disorders (IMD) are caused by deficient activity of an enzyme (or occasionally multiple enzymes) in a metabolic pathway. The deficiency ‘blocks’ the metabolic pathway and the clinical consequences of this arise because:

substrates prior to the ‘block’ accumulate and can be toxic;

essential products beyond the ‘block’ are not formed;

other compounds may be formed via alternative pathways which may be toxic.

Patients can present at any age: as neonates, throughout childhood, and in adulthood. The severity of the disorder may vary widely depending on the degree of enzyme deficiency. IMD occur in many pathways of amino acid, carbohydrate, lipid, and vitamin metabolism.

Treatment

Based on an understanding of the biochemistry. The mainstays of therapy are:

Therapeutic diet (see Table 36.1) to:

limit the intake of substrate that cannot be catabolized;

provide the product that cannot be formed.

Large doses of cofactor vitamins.

Medicines that conjugate with toxic metabolites so that the product is excreted in urine.

Enzyme replacement therapy is possible in a few disorders.

Liver transplant for some disorders.

IMD are rare and complex so it is essential that patients are managed in a specialist metabolic centre by a multi-disciplinary team including metabolic consultants, dietitians, and nurses, with supporting specialized laboratory services.

Newborn screening for IMD

England screens newborns for six IMDs using dried blood spots:

Phenylketonuria (since 1969)

Medium chain acyl-CoA dehydrogenase deficiency (MCADD) in England since 2004, and Northern Ireland, 2009

Maple syrup urine disease (MSUD) since 2015

Isovaleric acidaemia (IVA) since 2015

Glutaric aciduria Type 1 (GA1) since 2015

Homocystinuria—pyridoxine unresponsive (HCU) since 2015

Table 36.1 Summary of dietary management of some inherited metabolic disorders

Disorder Dietary management
Amino acid disorders
Classical phenylketonuria (PKU) Low phenylalanine diet + phenylalanine-free amino acid supplement
Maple syrup urine disease (MSUD)* Low leucine, isoleucine, valine diet + leucine, isoleucine, valine-free amino acid supplement
Isoleucine and valine supplements may be needed
Give an emergency regimen during illness containing suitable amino acid supplement + valine/isoleucine + glucose polymer*
Tyrosinaemia (TYR) type I and II Low tyrosine and phenylalanine diet + tyrosine, phenylalanine-free amino acid supplement
Type 1 also requires medication called nitisinone
Classical homocystinuria (HCU) Low methionine diet + methionine-free amino acid supplement. Cystine supplements may be necessary
Organic acidaemias*
Methylmalonic acidaemia (MMA)*
Propionic acidaemia (PA)*
Low protein diet (to limit methionine, threonine, valine, isoleucine intake). A methionine, threonine, valine, isoleucine-free amino acid supplement may be recommended if natural protein intake is below safe limits. Tube feeding is often required
Isovaleric acidaemia (IVA)* Low protein diet (to limit isoleucine intake)
Glutaric aciduria type I (GA1)* Low lysine or low protein diet (to limit lysine intake) + lysine-free, tryptophan-reduced amino acids before 6 years. Minimum safe protein diet post 6 years
Give an emergency regimen during illness containing suitable amino acid supplement + glucose polymer*
Urea cycle disorders*
Ornithine carbamoyl transferase deficiency over the counter (OTC)*
Citrullinaemia*
Argininosuccinic aciduria (ASA)*
Carbamoyl phosphate synthase deficiency (CPS 1 def)*
N-acetyl glutamate synthase deficiency (NAGS)*
Low protein diet (to limit waste nitrogen for excretion) + L-arginine supplements. Essential amino acid supplements may be needed if natural protein intake is below safe limits
Carbohydrate disorders
Classical galactosaemia Minimal galactose and lactose diet. Infant soya milk substitute. Calcium and vitamin D supplements may be needed.
Glycogen storage disease (GSD) type I* and type III* Frequent supply of exogenous glucose, provided as continuous overnight tube feeds or uncooked cornstarch before bed and 2-4 hourly daytime feeds or uncooked cornstarch
Type III: use of uncooked cornstarch and consider high protein diet
Fatty acid oxidation disorders*
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)*
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)*
Minimal long chain fat, ↑ CHO diet and medium chain triglyceride supplements. Frequent daytime feeding and continuous overnight tube feeds or uncooked cornstarch
Treatment of later presentation of VLCAD will be based on severity
Medium chain acyl-CoA dehydrogenase deficiency (MCADD)* Normal diet, avoidance of MCT products. Emergency regimen during illness. Base maximum fasting time on age:

0-4 m: 6 h

5-8 m: 8 h

9-12 m: 10 h

>12 m: 12 h

Familial hypercholesterolaemia
Type I hyperlipidaemia
Abetaliproteinaemia
Healthy eating, restricted saturated fat, replace with poly- and monounsaturated fat
Very low long chain fat diet (to tolerance). Medium chain triglycerides can be given
Very low long chain fat diet. Vitamin A and E supplements. Medium chain triglycerides not recommended

* Disorders requiring emergency regimen during metabolic stress such as intercurrent illnesses, e.g. diarrhoea, vomiting, ear infections, etc. (see image this chapter ‘Emergency regimens for IMD’, p. 820, for more detailed information).

Emergency regimens for IMD

Metabolic stress, e.g. intercurrent infections combined with poor oral intake and fasting, anaesthesia, or surgery, can precipitate severe metabolic decompensation in some IMD. Decompensation is caused by catabolism with concomitant ↑ production of toxic metabolites. An emergency regimen (ER) of glucose polymer solution is given to provide energy and help minimize the effects of catabolism. The basic ER can be started at home and is similar for all disorders:

Glucose polymer solution is given orally 2–3-hourly day and night or continuously via a tube.

Carbohydrate concentration of solution and volume given depends on age and weight (see Table 36.2).

Glucose polymers can be flavoured to improve palatability.

If an oral rehydration solution is prescribed for treatment of gastroenteritis, additional glucose polymer needs to be added to provide a final concentration of 10–12% carbohydrate. More concentrated solutions may exacerbate diarrhoea.

For some disorders, additional specific therapy is given such as drugs to promote excretion of toxic metabolites or amino acids to promote anabolism.

Patients and carers should be advised to call the metabolic team for advice if they start the ER.

If the ER is not tolerated, admission to the local hospital for tube feeding of ER or stabilization with IV fluids (10% dextrose) is often necessary.

Patients and/or carers should be given explicit, hand-held, written ER instructions that explain the disorder, hospital management, and provide contact details for the specialist metabolic centre.

For detailed information on emergency regimen protocols for use in hospital see: image…… http://www.bimdg.org.uk.

ER solutions are not nutritionally complete and prolonged use can result in protein malnutrition. The patient’s usual diet should at least start to be reintroduced after 24-48 hours of ER.

Table 36.2 Emergency regimens—composition and fluid volume for age

Age Glucose polymer concentration, % CHO Energy, kcal/100 mL Suggested daily fluid volume given as 2–3-hourly drinks/tube feeds
0–6 m 10 40 150 mL/kg
up to 1,200 mL/day maximum
7–12 m 10 40 120-150 mL/kg
up to 1,200 mL/day maximum
1–2 y 15 60 11–20 kg:
100 mL/kg for first 10 kg + 50 mL/kg for next 10 kg
20 kg:
100 mL/kg for first 10 kg + 50 mL/kg for next 10 kg + 25 mL/kg thereafter
up to 2,500 mL/day maximum
2–10 y 20 80
>10 y 25 100
Adults 25 100 35 mL/kg
up to 2,500 mL/day maximum

Phenylketonuria

Phenylketonuria (PKU) is caused by a deficiency of the enzyme phenylalanine hydroxylase that converts the essential amino acid phenylalanine to tyrosine. Phenylalanine (Phe) accumulates in plasma and is neurotoxic. Tyrosine, which is essential for the synthesis of protein and the catecholamine neurotransmitters, becomes deficient. Untreated, patients will develop severe mental retardation. Newborn screening for PKU was established in the UK in 1969. Patients are treated with a low Phe diet that is continued throughout childhood and into adulthood (diet for life is recommended). If an adult chooses to come off the low Phe diet, then dietary adequacy must be ensured. During preconception and pregnancy in women with PKU, a low Phe diet is essential to prevent damage to the unborn baby.

Low Phe diet—main principles

Restrict intake of dietary protein to maintain plasma Phe concentrations within recommended reference range for age (Table 36.3).

Give a Phe-free amino acid supplement (protein substitute). This is essential because Phe restriction limits natural protein intake to below that needed for normal growth:

Generous intakes of Phe-free amino acids are recommended: 0–2 years = 3.0 g/kg body weight/d; 3–10 years = 2.0 g/kg/d; >10 years = 1g/kg/d; maximum 80 g. Amino acid supplement is given three to four times throughout the day, combined with some measured Phe foods.

A range of age-dependent prescribable amino acid supplements is available. These vary in nutrient composition and presentation, e.g. infant formula, gels, juice, or milk-type drinks which need reconstitution, ready-made drinks, tablets, capsules (see image…… Chapter 38, ‘Prescription of nutritional products’ and British National Formulary).

Flavourings need to be added to improve palatability/acceptability of some, particularly older formulations.

Give a vitamin and mineral supplement to meet normal dietary requirements if not added to amino acid supplement or if taking inadequate amounts of amino acid supplement.

Provide daily Phe allowance. Daily Phe intake varies between patients and depends on the level of enzyme activity:

Phe prescribed is based on plasma Phe concentrations;

Phe intake is measured using a system of 50 mg Phe exchanges or 1 g protein exchanges if Phe content of food is unknown;

Phe is provided in breastmilk/infant formula for babies or low protein foods, e.g. potato, peas, sweetcorn, cereal, for older infants, children and adults;

Phe intake is divided evenly across the day.

Provide adequate energy intake for growth in children and adolescence from a combination of:

naturally very ↓ protein foods (e.g. pure fats, sugar, fruit, some vegetables);

special ↓ protein, prescribed manufactured foods, e.g. bread and flour mixes, pasta, rice, biscuits, crackers, chocolate, snack pots, cereals, burger and sausage mix.

Low Phe diet—monitoring

A low Phe diet is monitored by regular measurement of plasma Phe concentrations. See Table 36.3 for frequency of monitoring and recommended plasma Phe concentrations at different ages. Patients or carers collect blood samples for Phe analysis (usually on a dried blood spot card and send by first class post to the biochemistry lab). Ideally, blood should be taken at the same time, in the morning before the amino acid supplement. Patients and carers need to be promptly advised of any necessary dietary changes depending on plasma Phe results.

Reasons for high plasma Phe concentrations:

intercurrent illnesses;

too much dietary protein or Phe;

insufficient amino acid supplement;

unintentional use of non-PKU amino acid supplement or gluten-free, rather than low protein manufactured foods.

Reasons for low plasma Phe concentrations:

inadequate intake of protein or Phe;

growth spurt;

↑ requirement post-illness.

Table 36.3 Recommended reference ranges for plasma Phe concentrations and frequency of Phe monitoring in PKU*

Age, years Plasma Phe, mol/L Minimum frequency of monitoring
0–11 120–360 0-1 years weekly
1-11 years fortnightly
>12 120–600 Monthly
Preconception and pregnancy 120-360 Preconception weekly
Pregnancy twice weekly

* Source: data from van Spronsen, F.J., et al. (2017). Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. doi: 10.1016/S2213-8587(16)30320-5.

Further reading

British Inherited Metabolic Group. Available at: image…… www.bimdg.org.uk.

Dixon, M. (2014). Chapters 17-19. In: V Shaw (ed) Clinical paediatric dietetics 4th edn. Wiley-Blackwell, Oxford.

Saudubray, J.M., et al. (2016). Inborn metabolic diseases: diagnosis and treatment 6th edn. Springer-Verlag, Berlin.

Singleton, K. et al. (2019). Inherited metabolic disorders. In: J Gandy (ed) Manual of dietetic practice 6th edn. Wiley-Blackwell, Chichester.

Refsum’s disease

Refsum’s disease is a rare autosomal recessive disorder of lipid metabolism where the presence of a defective enzyme, phytanoyl-coenzyme A hydroxylase, results in accumulation of phytanic acid leading to neurological symptoms.

Treatment is based on restricting the dietary intake of phytanic acid from a typical intake of 50–100 mg/day to <10 mg/day, and minimizing release of endogenous phytanic acid.

Rich sources of phytanic acid:1 avoid in Refsum’s disease, e.g. beef, lamb, meat from ruminant animals (e.g. venison), dairy products (including cow’s and goat’s), fish and fish oils, baked products with unknown sources of fat.

Foods containing little phytanic acid: (or in bound form): acceptable in Refsum’s disease, e.g. poultry, pork, fruit, vegetables, seafood with very low-fat content, e.g. crab and prawns, cereal products (unless prepared with dairy or fish oil), eggs, soya milk, vegetable oils, and margarine made exclusively from vegetable oils.

Nutritional adequacy of the diet: must be checked to ensure sufficient energy and all other nutrients are provided.2 A low energy diet will lead to weight loss and the accompanying lipolysis will mobilize endogenous phytanic acid. If necessary, supplements should be provided during periods of intercurrent illness to ensure an adequate intake is maintained.

Caffeine: high intakes should be avoided as they are associated with hepatic lipolysis and phytanic acid release.

Adherence to the diet is associated with sustained reductions in serum phytanic acid and few acute complications that are associated with untreated Refsum’s disease. It is recommended3 that patients are reviewed 6-monthly and that dietary restrictions should be followed for life.


1Roca-Saavedra, P., et al. (2017). Phytanic acid consumption and human health, risks, benefits and future trends: A review. Food Chem. 221, 237-47.

2Baldwin, E.J. et al. (2016). Safety of long-term restrictive diets for peroxisomal disorders: vitamin and trace element status of patients treated for adult Refsum disease. Int. J. Clin. Pract. 70, 229-35.

3Baldwin, E.J. et al. (2010). The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J. Neurol. Neurosurg. Psychiatry 81, 954-7.